In cardiac tissue of cardiomyopathic patients, transforming growth factor-β(TGF-β), which has been demonstrated to stimulate cardiac fibrosis in animal models (Kuwahara, et al. Circulation, 2002, 106, 130), is increased (Li et al., Circulation, 1997, 96, 874). In the myocardial fibrotic area, it is known that mast cells are increased in number and may contribute to the development of fibroblast proliferation in cardiac tissues of patients with cardiomyopathy (Patella et al., Circulation, 1998, 97, 971). Chymase is a chymotrypsin-like serine protease contained in the secretory granules of mast cells. Although the precise physiological roles of Chymase have not been completely revealed, Chymase is known to transform angiotensin Ito angiotensin II and may contribute to activation of TGF-β, matrix proteases, and cytokines (Taipale et al., J. Biol. Chem., 1995, 270, 4689; Takai et al., Life Sci., 1996, 58, 591; Takai et al., Circulation, 1999, 100, 654). A potent and selective Chymase inhibitor may have potential use as a treatment of chronic heart failure, atherosclerosis, restenosis, and myocardial infarction by inhibiting local production of angiotensin II in the heart and release of TGF-β, two independent mediators of cardiac remodeling. Several small molecule Chymase inhibitors have been reported to be efficacious in the cardiomyopathic hamster model of heart failure (Takai et al. J. Pharmacol. Exp. Ther. 2003, 305, 17), in carotid artery injury by a balloon catheter in dogs (Takai et al. J. Pharmacol. Exp. Ther, 2003, 304, 841), and in the hamster left anterior descending coronary artery ligation model of heart failure (WO 03/018061).
An inhibitor may also have potential use for treatment of mast cell mediated diseases such as dermatitis, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary inflammation, since Chymase is implicated in microvascular leakage, neutrophil accumulation, the stimulation of mucus secretion, and the modulation of cytokines (He et al., Eur. J. Pharmacol., 1998, 352, 91). Indeed, Chymase inhibitors have demonstrated efficacy in animal models of abdominal aortic aneurysm (Tsunemi et al., J. Pharm. Exp. Ther., 2004, 309, 879), angiogenesis (Muramatsu et al., Brit. J. Pharm., 2002, 137, 554), pulmonary fibrosis (Sakaguchi et al., Eur. J. Pharm., 2004, 493, 173), adhesion formation (Okamto et al., Eur. J. Pharm., 2004, 484, 357), scleroderma (Shiota et al., Brit. J. Pharm., 2005, 145, 424), asthma and COPD (Garavilla et al., J. Biol. Chem., 2005, 280, 18001), and atopic dermatitis (Imada et al., Jpn. J. Pharm. 2002, 90, 214).